This is a renewal proposal to continue a study of DNA repair and its regulation and importance in carcinogenesis in the colon, and in dictating the effectiveness of genotoxic therapy. Two major objectives will be pursued in the next 3 years: First, DNA repair will be studied directly in colon mucosal cells, in comparison with other cell types, to determine the repair pathways present and their relative activities, and localize the effects of specific inhibitors with particular emphasis on inhibitors which have been found in fecal contents. These studies have now been established using freshly prepared colon cells and tumor cells in tissue culture. Secondly, we will explore the potential importance of promoters in colon carcinogenesis and will continue to explore the question of whether regulation of DNA repair may be one important mechanism of promotion. These studies will employ bile acids and other sterols found in colon contents as well as the "classic" promoters that have been used to enhance skin carcinogenesis. Those promoters which work for colon cells will be studied for their effects on DNA repair pathways. Concomitantly, different types of agents shown to be regulators of repair will be tested for promoting effects on colon cells. The colon may well be an excellent site for studying promoters and their mechanisms of action.